Modeling the Menthol Binding Pocket Within TRPM8 Ion Channel

Abstract

Menthol is a natural substance that induces a cooling sensation. It is common in remedies used to soothe aching muscles. The menthol receptor, TRP melastatin 8 (TRPM8), is one of eight members of the TRP protein superfamily and is activated by physical stimuli such as cold and chemical stimuli such as the ligand menthol. The menthol binding takes place within the putative menthol-binding pocket, located within the transmembrane domain of TRPM8 channel, however, due to a lack of TRPM8 structure with menthol bound, the binding configuration of menthol is unknown. The Summit Country Day School MSOE Center for Biomolecular Modeling MAPS Team used 3D modeling and printing technology to examine the structure-function relationship of the menthol binding pocket on TRPM8. The menthol-binding pocket can be found within the transmembrane domain of the TRPM8 channel near Y745 and R842 within the S1–S4 domain. Computational and functional analysis have suggested that menthol uses its hydroxyl group “hand” to grab the R842 side chain, and its isopropyl group “legs” to stand on I846 and L843. Menthol's hydroxyl group binds with R842 likely through a hydrogen bond, while its isopropyl legs stand on residues on S4 through Van Der Waal Interactions. This binding causes a conformational rearrangement of the binding pocket of of amino acids Y745, R842 and D802, allowing ions to pass through the channel. TRPM8 may be involved in many pathological processes such as cold hyperplasia, irritable bowel disease, prostate cancer, and migraines. Therefore, understanding the binding site of menthol in the TRPM8 channel may be important not only for designing potential drug targets but also the mechanism of regulating TRPM8 activity.